Immune-Mediated Diseases

In a Nutshell

Objectives

Describe the epidemiology, clinical

presentation, pathogenesis and

pathologic changes of autoimmune

diseases, including lupus erythematosis,

rheumatoid arthritis, vasculitis,

temporal arteritis and Wegener's

granulomatosis

Systemic Lupus Erythematosus

Systemic lupus erythematosus:

clinical features

Febrile, multisystem inflammatory disease

Variably affects wide range of organs and tissues,

especially skin, kidneys, serosal surfaces, joints, heart

Clinical course highly variable, often with multiple

exacerbations and remissions

Especially prevalent in young women, black Americans

Prevalence: up to 1 to 2,500 persons

Systemic lupus erythematosus:

pathogenesis Autoantibodies develop against a variety of antigens:

Nucleoproteins / nucleic acids

DNA

histones

nonhistone RNA-binding proteins

Blood cells

erythrocytes

platelets

lymphocytes

Phospholipids (e.g., “lupus anticoagulant”)

Systemic lupus erythematosus:

pathogenesis

Antigen-antibody immune complexes form

Complexes deposit in numerous sites, initiate complement cascade, and trigger inflammation

Antibody bound to

cells leads to lysis

via complement-

mediated

cytotoxicity or

ADCC

Type III Hypersensitivity Type II Hypersensitivity

Systemic lupus erythematosus:

pathogenesis

Possible causes of autoantibody

production

Intrinsic B cell defect

Excessive helper T cell activity

Deficient suppressor T cell activity

Rheumatoid Arthritis

Rheumatoid arthritis: clinical features Systemic, chronic inflammatory disease

Principally affects joints: severe, deforming,

symmetric polyarthritis

May involve other organs and tissues (e.g.,

skin, heart, blood vessels, muscles, lungs)

Onset generally in 3rd or 4th decade

Especially prevalent in women

Prevalence: approximately 1% of population

Rheumatoid arthritis: pathogenesis

Activation of CD4+ T cells, possibly

by arthritogenic infectious agent

Lymphokine production

Rheumatoid arthritis: pathogenesis

Activation of

macrophages and other

inflammatory cells, with

subsequent tissue

destruction

Activation of B cells,

including some

producing autoantibodies

(e.g., IgG anti-IgG, or

rheumatoid factor);

immune complex

formation

Type IV hypersensitivity Type III hypersensitivity

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You know how a few slides ago he described it as "severe" and "deforming"? ....Yea. Note the ulnar deviation.

Vasculitis

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Lots of things can cause inflammation of the blood vessels (e.g. infectious agents), today we're only going to talk about immune-mediated ones.

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Shows how different vasculitises are distributed, note that there is an overlap in which types of vessels the different diseases hit (e.g. multiple different diseases affect arterioles).

Hypersensitivity (leukocytoclastic)

vasculitis

Henoch-Schönlein purpura

Serum sickness

Connective tissue diseases

(e.g., systemic lupus erythematosus)

Mixed cryoglobulinemia

Chronic active hepatitis B

Lymphoproliferative disorders

Reactions to drugs, pathogens

Hypersensitivity vasculitis

Vessels involved

Venules

Capillaries

Arterioles

Hypersensitivity vasculitis: clinical

features

Skin lesions (palpable purpura,

macules, vesicles, necrosis,

ulceration)

Vascular lesions in other organs

(lungs, brain, kidneys,

gastrointestinal tract) with variable

manifestations (e.g.,

glomerulonephritis, infarcts)

Hypersensitivity vasculitis:

pathogenesis

1. Antibody response to exogenous antigen or autoantigen

2. Immune complex formation

3. Deposition of immune complexes in vessels (especially venules)

Hypersensitivity vasculitis:

pathogenesis

4. Complement fixation;

generation of chemotactic

fragments (e.g., C5a)

5. Attraction of inflammatory cells

(especially neutrophils); tissue

destruction

Hypersensitivity vasculitis:

pathogenesis

4. Complement fixation; generation of chemotactic fragments (e.g., C5a)

5. Attraction of inflammatory cells (especially neutrophils); tissue destruction

Type III hypersensitivity

Hypersensitivity vasculitis: histology

Infiltration of vessel walls by neutrophils, neutrophil degeneration (leukocytoclasis), vessel wall necrosis

Immune complex deposition

Immunoglobulin components may vary:

Henoch-Schönlein purpura: IgA

Systemic lupus erythematosus: mixed

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Cartoon demonstrated what's on the previous slides. Just to recap: We have immune-complexation in the blood, it deposits in the small vessels, induces inflammation and cell destruction, and possibly eventually rupture (in the venule).

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This is a purpura stained with fluorescent anti-IgA-antibodies (This pt has Henoch-Schonlein).

Temporal arteritis

(giant cell arteritis; cranial

arteritis)

Temporal arteritis

Vessels involved

Elastic tissue-rich major arteries

(branches of carotid artery, including temporal and ophthalmic arteries; less frequently, aorta and other arteries; heart and lungs generally spared)

Temporal arteritis: clinical features

Severe headache or facial pain, often unilateral and

most intense along temporal artery

Visual disturbances (diplopia, blindness)

Constitutional symptoms (fever, fatigue, weight loss)

Associated in approximately half of cases with

polymyalgia rheumatica (syndrome of pain and

muscle stiffness)

Most common in older adults

Male:female ratio 1:2 or 1:3

Temporal arteritis: pathogenesis

Unknown; may involve type IV

hypersensitivity to antigens

associated with elastic tissue or

smooth muscle

Familial clustering of cases and

predilection for white patients

suggests genetic component

Temporal arteritis: histology

Two histologic patterns:

1. Granulomatous inflammation with multinucleate

giants cells, centered on internal elastic lamina, which is often disrupted

2. Mononuclear inflammatory infiltrate without giant cells, occasionally with fibrinoid necrosis

Vascular lumen often obliterated or thrombosed

In healing phase, vessel may be largely replaced with fibrous tissue

Segmental lesions alternating with unaffected areas may produce “nodular” morphology

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A temporal artery of a temporal arteritis pt. Note the inflammation of the muscular layer and the near-completely occluded lumen.

Wegener’s granulomatosis

and Microscopic polyangiitis

Vessels involved

Venules, capillaries, arterioles

Small to medium sized arteries

Wegener’s granulomatosis: clinical

features

Upper respiratory inflammation (e.g., sinusitis, often severe, with bloody nasal discharge)

Pulmonary symptoms (cough, hemoptysis, shortness of breath)

Renal manifestations (hematuria, rapidly progressive renal failure)

Lesions involving other organs (eyes, skin, occasionally heart)

Most common in middle aged adults

Males more commonly affected

Microscopic polyangiitis: clinical

features

Variable, can involve different organ systems

Isolated renal disease with hematuria, renal insufficiency is a common presentation

Pathogenesis

Generation of autoantibodies to neutrophils (anti-neutrophil cytoplasmic antibodies, or ANCA), neutrophil activation, tissue damage

Patients with Wegener’s granulomatosis often have “cytoplasmic” ANCA (c-ANCA) (anti-proteinase 3)

Patients with microscopic polyangiitis often have “perinuclear” ANCA (p-ANCA) (anti-myeloperoxidase)

Wegener’s granulomatosis: histology

Necrotizing granulomas of upper respiratory tract (ear, nose, sinuses, throat)

Necrotizing granulomatous vasculitis in other organs, especially lungs

Necrotizing glomerulonephritis, often with crescents

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Pt. lung piece from someone with Wegener's

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This is a lung slide from a Wegener's pt w/ a stain for elastic tissue. The wall of the blood vessel has been destroyed.

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Lol, he didn't get to talk about Kawaski disease (it's a real thing, supposedly) but he meant to talk about it here.